Original Article

SYNTHESIS OF NOVEL HETEROCYCLIC QUINOLONE COMPOUND FOR

ANTI -TUBERCULAR ACTIVITY

Rahul K. Godge 1 , Rahul Kunkulol 2

1
Pravara Rural College of Pharmacy,
2
Pravara Institute of Medical Sciences, Loni BK - Rahata, Ahmednagar, 413736 (M.S.). India .

ABSTRACT

In last few decades, though significant progress has been made in the treatment and control strategies of tubercular
infections by introducing new diagnostic and monitoring tools and combination therapy, it still continues to be se-
vere problem. The need of study was only because of there are many drugs in market to treat infection but most of
the drugs are showing resistance because of the same it is difficult to treat the infection. In this study we chosen
quinolone nucleus for study and over it. Thus with the aim of developing novel molecule with improved potency for
treating Mycobacterium tuberculosis H37Rv strain infections and with decreased probability of developing drug re-
sistance. Methodology: The synthesis of Quinolone derivatives, starting from substituted aniline and ethyl acetoace-
tate, by conventional organic reaction and results of investigations of their anti-mycobacterial activity. Results: MICs
of the synthesized compounds are compared with existing drugs Cytotoxicity. The substituted quinolones are synthe-
sized by taking mixture of 7-substituted-2-(3-chloro-2-oxopropyl) quinolin-4(1H)-one and different secondary
amines. Many compounds have shown promising activity while some were inactive. Conclusion: It was found that
Compound A1, A3, B1, B3, have shown promising anti tubercular activity whereas compound A 2, A4,B2,B4 were showing
moderate anti tubercular activity against std. Streptomycin.

KEYWORDS: Quinolone derivative; Well diffusion method; Spectral analysis; Elemental analysis.

drugs and chеmothеrapy) arе at a grеatеr risk for

INTRODUCTION
Microbial infections remain the major cause of death
over the world. Emergence of multi-drug resistant to
different infectious organisms like M. tuberculosis
made the condition most alarming.[1-2] Tuberculosis,
MTB, or TB is a deadly infectious disease caused by
various strains of mycobacteria; usually Mycobac-
tеrium tuberculosis. According to World Health Organ-
ization (WHO) TB is a global pandemic, which has be-
come an important world-wide public health menace
with one-third of the world’s population infected by
the TB bacillus. Most infections do not havе symptoms,
known as latеnt tubеrculosis and about onе in tеn
latеnt infеctions еvеntually progrеssеs to activе disеasе
which, if lеft untrеatеd, kills morе than 50% of thosе
so infеctеd. Pеoplе with wеak immunе systеms (thosе
with HIV/AIDS, thosе rеcеiving immunosupprеssivе
DOI: 10.31878/ijcbr.2018.43.10
eISSN: 2395-0471
pISSN: 2521-0394
dеvеloping TB disеasе. Thеrе is currеntly a growing
concеrn about thе progrеss and sprеad of multidrug
and еxtеnsivеly drug resistant tuberculosis (MDR/XDR
-TB), which has thе potеntial to paralyzе TB carе
schеmеs. Thе focal thеmе of this thеsis is thе
еxploration of nеw stratеgiеs in thе fiеld of modеrn
drug discovеry for thе dеvеlopmеnt of nеw drugs,
which are capablе of ovеrcoming MDR/XDR-TB. The
present work was aimed to synthesized new compound
and evaluate it for antituberculer activity. Therefore,
there is an urgent demand for a new class of antimicro-
bial agent with a different mode of action and it led
medicinal chemists to explore a wide variety of chemi-
cal structures.
Quinoline was first isolated from coal tar in 1834, it was
also recognized as pyrolytic degradation product of
cinchonamine, an alkaloid closely related to quinine[3-
6]. The name quinoline was derived from quina, a
Spanish version of a local South American name for the
bark of quinine-containing cinchona Species. Several
Synthetic anti-malarial drugs are based on the quino-
line nucleus, Chloroquine is an example. Several antibi-
otics like fluro-quinolones now in clinical use were 4-
quinolone-based antibiotics.[7-10] Quinoline is a color-

Correspondence: Mr. Rahul Keshav Godge, Pravara Rural College of Pharmacy, Loni BK, Tal- Rahata,
Dist: Ahmednagar, Maharashtra-413736, India. E-mail: rahul_godge@rediffmail.com
International Journal of Clinical and Biomedical Research. © 2018 Sumathi Publications.
This is an Open Access article which permits unrestricted non-commercial use, provided the original work is properly cited. 44
Rahul K et al.  Synthesis of novel heterocyclic Quinolone compound for anti -tubercular activity.

less liquid of bp. 2370C. It turns yellow on standing and tallized.

has pyridine like smell.Miscible with most organic sol-
vents and dissolves in water to about 0.7 % at room
temperature. Slightly weaker base (pKa= 4.94) than
pyridine (pKa= 5.2). It reacts with acid to yield salts
which are sparing soluble in water[11-12].
Compounds containing quinolones exhibiting variety of
pharmacological and biological activities[13-25].
Spectral Data
A1- IR (KBr): 3487.07 (-N-H str), 3032.16 (Ar-H
str), 2841 ( CH str), 1721 (-C=O str), 1685 (CO str am-
ide), 1160 (-C-N str), 801(-C-Clstr) NMR: d8.5-8.(0 1H, S-
NH), 7.91-7.87 (4H ,m-Quinolone), 7.37-6.97 4H,m -Ar-
CH 3.81-3.12 2H,d -CH2

Experimental A2- IR (KBr): 3487.07 (-N-H str), 3135(Ar-H str),

General: The nucleus and its derivatives were analyzed
by different ways. The melting points were recorded on
electrothermal apparatus and are uncorrected.(IR)
spectra were determined on Bruker IFS-66 FTIR (Bruker
Bioscience, USA) using KBr pallets and wave number (í)
was reported in cm-1. 1H NMR spectra on a Bruker
Avance 300 MHz instrument using DMSO as solvent
using TMS as internal standard; the chemical shifts (δ)
were reported in ppm with coupling constants (J) are
given in Hz. Signal multiplicities were represented by s
(singlet), d (doublet), t (triplet), ds (double singlet), dd
(double doublet), m (multiplet) and bs (broad singlet.
Elemental analysis was performed on a Hera- cus CHN-
Rapid Analyzer. Analysis indicated by the symbols of
the elements of functions was within ±0.4% of the the-
oretical values. The purity of the compounds was
checked on silica gel coated Al plates (Merck).
Synthesis of 2-methyl-7-substituted-4-quinolone
2561 ( CHstr), 1721 (-C=O str), 1685 (CO str amide),
1353 (–SO2NH2 str), 1200 (-C-N str) 801(-C-Clstr)
A3- IR (KBr): 3372 (-N-H str), 3032(Ar-H str),
2850 ( CHstr), 1720 (-C=O str), 1685 (CO str amide),
1200 (-C-N str) 780 (-C-Clstr)
A4- IR (KBr):3420 (-OH str), 3380 (-N-H str),
3020(Ar-H str), 2862 ( CHstr), 1700 (-C=O str), 1685 (CO
str amide), 1230 (-C-N str) 759 (-C-Clstr)
B1- IR (KBr):3367 (-NH str), 3021 (-Ar-H str),
2848(-CH str), 1728 ( -C=O str), 1655 (CO str amide),
1157 (-C-N str) 662 (-C-Br str)
B2- IR (KBr):3367 (-NH str), 3021 (-Ar-H str),
2848(-CH str), 1728 ( -C=O str), 1655 (CO str amide),
1353 ((–SO2NH2 str))1157 (-C-N str) 662 (-C-Br str)
B3- IR (KBr): 3372 (-N-H str), 3032(Ar-H str),
2850 ( CHstr), 1720 (-C=O str), 1685 (CO str amide),
1200 (-C-N str) 645 (-C-BR str)

A mixture of (0.01 mol) substituted anilines and (0.01
mol) ethyl acetoacetate was stirred, was heated on
oil bath at 1800C for two hours, The crude solid was
filtered, dried and recrystallized from ethanol .
2. Synthesis of 7-substituted-2-(3-chloro-2-oxopropyl)
quinolin-4(1H)-one (II)
B4- IR (KBr):3420 (-OH str), 3370 (-N-H str),
3020(Ar-H str), 2850 ( CHstr), 1690 (-C=O str), 1680 (CO
str amide), 1230 (-C-N str) 650 (-C-Br str)
Anti-tubercular activity: The compounds were tested
in-vitro for their anti-tubercular activity against H37Rv
Strain.

An quantity of 0.01 moles of I was dissolved in 25 ml of
glacial acetic acid. If did not dissolve completely, the
mixture was slightly warmed. The solution was cooled
in ice bath with stirring. To this chloroacetyl chloride
(0.12 mole) solution added drop wise. To prevent the
occurrence of vigorous reaction the temp was main-
tained at 0oC then reaction was heated for 30 mins
after this cool the mixture and pour over crushed ice
white product was separated by filtration. The product
was washed with 50% aqueous acetic acid and finally
with water. It was recrystallized.
Method: Alamar Blue Dye: The anti-tubercular screen-
ing was carried out by Middle brook 7H9 agar medium
against H37Rv Strain. Middle brook 7H9 agar medium
was inoculated with Mycobacterium tuberculosis of
H37Rv Strain. The inoculated bottles were incubated for
37°C for 4 weeks. At the end of 4 weeks they were
checked for growth.
RESULT
Scheme: (A1-A4, B1-B4)
O O
NH2

+
3. Synthesis of derivatives of substituted 4-quinolones R
H 3C

ethyl acetoacetate
O CH 3

III Reflux

A mixture of 0.01 mole of each II were taken in dry 250

ml round bottom flask separately to this distilled alco- R

(I)
N
H
CH3

hol is added as solvent and to this different secondary ClCoCH2Cl GAA

amines were added in 0.01 mole concentrations and O

R'-NH2
O

refluxed for 2 hour after reflux add reaction mixture to Reflux for 2hrs

crushed ice precipitation formed is filtered and recrys- R N

COCH2Cl
R N
H
COCH2NHR

Int. j. clin. biomed. res. 2018;4(3):44-49. 45

Rahul K et al.  Synthesis of novel heterocyclic Quinolone compound for anti -tubercular activity.

Table 1. Derivative compounds

R
Compounds R’

O
N
A1 -Cl
-HN NH

-HN SO2NH2
A2 --Cl

-HN N
A3 --Cl
N

-HN COOH
A4 --Cl

O
N
B1 - Br
-HN NH

-HN SO2NH2
B2 - Br

-HN N
B3 - Br
N

-HN COOH
B4 - Br

Int. j. clin. biomed. res. 2018;4(3):44-49. 46

Rahul K et al.  Synthesis of novel heterocyclic Quinolone compound for anti -tubercular activity.

Table 2. Anti-tubercular activity of substituted 4-quinolones compounds

Comp 100 50 25 12.5 6.25 3.125 1.6 0.8 0.4 0.2
ID

A1 S S S S S S S R R R
A2 S S S S R R R R R R
A3 S S S S S S S S R R
A4 S S S R R R R R R R
B1 S S S S S S S R R R
B2 S S S S S R R R R R
B3 S S S S S S S S S R
B4 S S S S R R R R R R
Strepto- S S S S S R R R R R
mycin

Table 3. Analytical data of the compound

Elemental analyses
Comp. Mol. Mol. m.p. Yield Rf val- Calcd. (Found)
Code Formula Wt. °C % ue
C H N

A1 C18H15ClN4O3 370.78 180-182 79.85 0.50 58.31 4.08 15.11

A2 C18H16ClN4O4S 405.85 142-144 72.53 0.57 53.27 3.97 10.35

A3 C17H13ClN4O3 356.76 130-132 69.52 0.53 57.23 3.67 15.70

A4 C18H22ClN3O4 379.83 136-138 74.54 0.50 56.92 5.84 11.0

B1 C18H15BrN4O3 415.24 110-112 75.34 0.61 52.06 3.64 13.49

B2 C18H16BrN3OS 450.30 140-142 74.67 0.59 48.01 3.58 9.33

B3 C17H13BrN4O3 401.21 112-114 72.23 0.65 50.89 3.27 13.9

B4 C18H22BrN3O4 424.28 136-138 62.12 0.64 50.95 5.23 9.90

Int. j. clin. biomed. res. 2018;4(3):44-49. 47

Rahul K et al.  Synthesis of novel heterocyclic Quinolone compound for anti -tubercular activity.
Figure 1. IR Spectra of A1
Figure 2. NMR Spectra of A1
DISCUSSION:
In the present research work, we have synthesized 8
new substituted 4-quinolones derivatives as explained
in the scheme. The purity of the compounds was
checked by TLC and melting point. Structures of these
compounds were confirmed by IR, 1HNMR and ele-
mental analysis. The synthesized compounds were sub-
jected to anti tubercular activity by Alamar Blue Dye
method against the standard streptomycin.
Compound A1, A3, B1, B3 have shown promising an-
titubercular activity against streptomycin at concentra-
tion of 1.6 mcg/ml by interpreting data of MIC. With
the suitable molecular modification and manipulation
with possible SAR studies of these compounds, promis-
ing anti tubercular agents can be obtained. [26, 27].
CONCLUSION
The substituted quinolones are synthesized by taking
mixture of 7-substituted-2-(3-chloro-2-oxopropyl) quin-
olin-4(1H)-one and different secondary amines. It was
found that Compound A1, A3, B1, B3, have shown promis-
ing anti tubercular activity whereas compound A2,
A4,B2,B4 were showing moderate anti tubercular activi-
ty against std. Streptomycin.
Acknowledgement: Authors are thankful to Dr. Bhatt
Int. j. clin. biomed. res. 2018;4(3):44-49.
Laboratory for the antitubercular activity data and Pun-
jab university for providing spectral and elemental
analysis.
REFERENCES
1. Ania AE, Idokob J, Dalyopc Y B. Pitmangd SLT. Article
title. Roy. Soci. Trup. Med. 2009;103:67.
2. Said HA, Abdel GS, Morlock G, Cooksey RC. Article
title Int. J. Infect. Dis.2009;,13, 673.
3. Antimicrobial - Definition from the Merriam-
Webster Online Dictionary. http://www.merriam-
webster.com/dictionary/Antimicrobial. Retrieved
2009-05-02.
4. John HK, John MB. Wilson and Gisvold’s Text book
of Organic medicinal and Pharmaceutical Chemistry.
11th Edition, Philadelphia: Lippincott Williams and
Wilkins; 2004: 299-301.
5. Rang HP, Dale MM, Ritter JM, Moore P K. Pharma-
cology. 5th Edition, New Delhi: Elsevier India Pvt Ltd;
2003: 667-72.
6. Silverstein SC, Stienman RM, Cahhn ZA. Endocytosis.
Ann. Rev. Biochem. 1977; 46: 669-72.
7. Stephonson TJ. Inflammation. In: Underwood JCE.
General and Systemic Pathology. 4th Edition, Lon-
don: Churchill Livingstone. 2004: 201-22.
8. Baxter JD, Rosseau GG. Glucocoticoid hormone ac-
tion: an overview. Monogram. Endocrinal. 1979;
12:1-24.
9. Vinay Kumar, Cotran RD, Robbins S. Basic Pathology.
6th Edition, Bangalore: Prism Book Pvt Ltd; 1997: 25
-46.
10. Hardman JG, Limbird LE. Goodman Gilman’s The
Pharmacological Basis of Therapeutics. 10th edition,
New York: McGraw-Hill Medical Publishing Division;
2001: 687-730.
11. John HK, John MB. Wilson and Gisvold’s Text book
of Organic medicinal and Pharmaceutical Chemistry.
11th Edition, Philadelphia: Lippincott Williams and
Wilkins; 2004: 818-22.
12. Nugteren DH, Hazelhof E. Isolation and properties
of intermediates in prostaglandin biosynthesis. Bio-
chem. Biophysics. Acta 1973; 326: 448-461
13. Chun MW, Olmstead KK, Choi YS, Chong OL, Chong-
Kyo L, Joong HK, et al. Synthesis and biological activ-
ities of truncated acridone: Structure-activity rela-
tionship studies of cytotoxic 8-hydroxy-4-quinolone.
Bioorganic & Medicinal Chemistry Letters. 1997;7
(1): 789-92.
14. Hong C, Kim S, Kim Y. Novel 5-amino-6-
methylquinolone anti-bacterial: A new class of non-
48
Rahul K et al.  Synthesis of novel heterocyclic Quinolone compound for anti -tubercular activity.

6-fluoroquinolones. Bioorganic & Med. Chemistry
Letters 1997;7(14):1875-1878.
15. Srivastava S, Srivastava SK , Shukla A , Chauhan P ,
Purlet S. Synthesis and the amides of methemoglo-
bin toxicity of 6/7 mono or disubstituted quinolone.
Bioorganic & Med. Chemistry Letters 1999 9: 25-30.
16. Masahiko H, Hiroto K, Tetsushi K, Tomio K , Tomoaki
K. Synthesis and anti-HIV activity of arylpiperazinyl
fluoroquinolones: a new class of anti-HIV agents.
Bioorganic & Med. Chemistry Letters.1999; 9: 3063-
3068.
17. Fukui H, Shibata T, Naito T, Nakano J, Maejima T,
Senda H, et al. Synthesis and Antibacterial Activity
of Novel 7-(3-Substituted-3 or 4-trifluoromethyl- 1-
pyrrolidinyl)-8-methoxyfluoroquinolones.
Bioorganic & Med. Chemistry Letters 1998; 8: 2833-
38.
24. Sriram D, Yogeeswari P, Basha JS, Radhab DR, Naga-
raja V. Synthesis and antimycobacterial evaluation
of various 7-substituted ciprofloxacin derivatives.
Bioorganic & Medicinal Chem. 2005; 13: 5774–78.
25. Lucero BA, Gomes CR, Frugulhetti IC, Faro LV,
Alvarenga L, Maria C. Synthesis and anti-HSV-1
activity of quinolonic acyclovir analogues.
Bioorganic & Med. Chemistry Letters 2006; 11: 1010
–13.
26. Farhanullah, Yeon Kim S, Yoon EJ, Choi EC,
Sunghoon K, et al. Design and synthesis of quino-
linones as methionyl-tRNA synthetase inhibitors.
Bioorganic & Medicinal Chem. 2006; 14: 7154–59
27. Sephra N. Rampersad. Multiple Applications of Ala-
mar Blue as an Indicator of metabolic Function and
Cellular Health in Cell Viability Bioassays. Sensors
(Basel). 2012;12(9): 12347–12360.

18. Robert J, Kerns RJ, Michael J, Glenn WR, Vaka F,

Richard GR, et al. Piperazinyl-Linked Fluoroquino-
lone Dimers Possessing Potent Antibacterial Activity
Against Drug-Resistant Strains of Staphylococcus
aureus. Bioorganic & Med. Chemistry Letters 2003;
13: 1745–49.

19. Foroumadi A, Soltani F, Moshafi MH, Ashraf-Askari

R. Synthesis and in vitro antibacterial activity of
some N-(5-aryl-1,3,4-thiadiazole-2-yl)piperazinyl
quinolone derivatives. II. Farmaco 2003; 58: 1023-
28.

20. Xia Y, Yang Z, Peng X, Bastow KF, Nakanishi Y, Priya

N.. Antitumor Agents. Part 226: Synthesis and Cyto-
toxicity of 2-Phenyl-4-quinolone Acetic Acids and
Their Esters. Bioorganic & Med. Chemistry Letters
2003; 13: 2891–93.

21. Scott HW, Marianne CTG, Murali D, Shen Z, Pitts

WJ, Junqing G, et al. Novel inhibitors of IMPDH a
highly potent and selective quinolone-based series.
Bioorganic & Med. Chemistry Letters 2003; 13(3),
543-46.

22. Piyasena H, Nathan C, Min D, Joanne T, Christopher

G, Boissard, et al. The synthesis and structure–
activity relationships of 3-amino-4-benzylquinolin-2-
ones: discovery of novel KCNQ2 channel openers.
Bioorganic & Med. Chemistry Letters 2004; 14: 1615
–1618.

23. Qun L, Woods KW, Wang W, Nan-Horng L, Claiborne

A, Wen-zhen G. Design, synthesis, and activity of
achiral analogs of 2-quinolones and indoles as non-
thiolfarnesyl transferase inhibitors. Bioorganic &
Med. Chemistry Letters 2005; 15: 2033–39.

How to Cite this article: Rahul K. Godge, Rahul Kunkulol. Synthesis of novel heterocyclic Quinolone compound for
anti -tubercular activity. Int. j. clin. biomed. res. 2018;4(3): 44-49.

Int. j. clin. biomed. res. 2018;4(3):44-49. 49